1. Field of the Invention
This invention relates to synthesis of no-carrier-added (NCA) aryl [.sup.18 F]fluorides by utilizing nucleophilic aromatic substitution of aromatic rings containing electron donating groups in addition to electron withdrawing and leaving groups. More specifically, this invention has been applied to the synthesis of high specific activity (+) and (-)-6-[.sup.18 F]fluoronorepinephrine by the nucleophilic aromatic substitution reaction, and this compound has been applied to study baboon heart metabolism in vivo using positron emission tomography (PET).
2. Background of the Related Art
Positron emission tomography (PET) is an in vivo imaging modality which measures the spatial and temporal distribution of positron emitter labeled compounds and their labeled metabolities in a volume element of living tissue; for example see: Fowler et al., in Annual Reports In Medicinal Chemistry, 24, 277, Allen (Ed.), Academic Press Inc., New York (1989). Although the heart has been extensively studied with PET, it has been examined mainly from the perspective of assessing perfusion and substrate metabolism; see, for example Jacobson, JAMA, 259, 2438 (1988). However, the neuronal integrity of the heart is also important in assessing cardiac physiology and pathophysiology; see, Eisenhofer et al., J. Clin. Sci., 76, 171 (1989); and Rose et al., J. Clin. Invest., 76, 1740 (1985). There also has been an interest in probing this function in vivo by using external imaging, beginning with the synthesis of [.sup.11 C]norepinephrine in the early 1970's, as reported by Fowler et al., J. Med. Chem., 17, 246 (1974); and Fowler et al., Radiopharmaceuticals, 196, Subramanian et al. (Eds.), The Society of Nuclear Medicine, Inc., New York (1975).
Fluorine-18, because of its ready availability and relatively long half life and low positron energy, is a very attractive nuclide for PET studies. However, because of the inherent difficulties in the formation of carbon-fluorine bonds, its incorporation into organic molecules and labeling with fluorine-18 remains a challenge, see Kilbourn, "Fluorine-18 Labeling of Radiopharmaceuticals", Nuclear Science Series, NAS-NS-3203, 1-149, National Academy Press, Washington, D.C. (1990). Prior to the present invention, the only methods so far described for introducing F-18 into an aromatic ring bearing the catecholamine moiety require the use of low specific activity electrophilic fluorination reagents derived from F-18 elemental fluorine.
Recently, interest in studies related to the neuronal integrity of the heart has intensified with the development of [.sup.18 F]fluorometaraminol reported by Mislankar et al, J. Med. Chem., 31, 362 (1988), and [.sup.11 C]m-hydroxyephedrine reported by Haka et al., J. Nucl. Med., 30, 767 (1989). Both compounds are metabolically stable, false neurotransmitters for norepinephrine. These tracers share the same uptake and storage mechanisms as norepinephrine and provide excellent images of the neuronal distribution in the dog heart, as reported by Wieland et al., J. Med. Chem., 33, 956 (1990), and by Rosenspire et al. Nucl. Med. Biol., 16, 735 (1989); and in the human heart, as reported by Schwaiger et al., Circulation, 82, 457 (1990), and Kopin, Circulation, 82, 646, (Ed. Viewpoint) (1990). Ring-fluorinated catecholamines such as 6-fluoronorepinephrine synthesized by Kirk et al., J. Med. Chem., 22, 1493 (1979) and Chiueh et al., J. Pharmacol. Exp. Ther., 225, 529 (1983); and 6-fluorodopamine synthesized by Kirk, J. Org. Chem., 41, 2373 (1976), and Eisenhofer et al., J. Pharmacol. Exp. Ther., 248, 419 (1988), have been shown to share the same presynaptic mechanisms for the uptake, storage, and synthesis as the parent molecules. Recently 6-[.sup.18 F]fluorodopamine has been synthesized by electrophilic fluorination and used in PET studies of the canine heart, as reported by Goldstein et al., Circulation, 82, 359 (1990).
In spite of the fact that both [.sup.18 F]fluorometaraminol and [.sup.18 F]dopamine display binding properties appropriate to their use in PET studies of myocardial innervation, their vasoactivity results in hemodynamic effects when these tracers are administered in vivo, thus limiting their application in humans, see: Goldstein et al. (1990), supra; and Mislankar et al. (1988), supra. Clearly, a route to high specific activity .sup.18 F-labeled catecholamines is needed so that the full potential of this class of compounds as neuronal imaging tracers can be objectively assessed. For these reasons, the inventors have examined the feasibility of preparing .sup.18 F-labeled catecholamines in high specific activity using [.sup.18 F]fluoride and nucleophilic aromatic substitution.
Nucleophilic aromatic substitution by fluoride ion has become one of the most useful labeling techniques utilizing fluorine-18, a positron emitter with a 110 minute half life. The mechanism and conditions necessary for successful substitution were the subject of a series of papers, Cacace et al., J. Label. Cmpds. Radiophram., 18, 1721 (1981); Attina et al. J. Chem. Soc. Chem. Commun., 108 (1983); Attina et al., J. Label. Cmpds. Radiopharm., 20, 501 (1983); and Angelini et al., J. Fluorine Chem., 27, 177 (1985). These techniques now have widespread application in their original or in their modified form as reported by Shiue et al., J. Label. Cmps. Radiopharm., 21, 533 (1984); Lemaire et al., Int. J. Appl. Radiat. Isot., 38, 1033 (1987); and Haka et al., J. Label. Cmpds. Radiopharm., 27, 823 (1989). The leaving group in the substitution reaction on an aromatic ring is usually nitro or -.sup.+ NMe.sub.3 and the necessary electron withdrawing group to effect the reaction can be RCO, CN, NO.sub.2 etc. There are, however, numerous important radiopharmaceuticals with electron donating substituents, in addition to the electron withdrawing substituents, which can make the substitution reaction proceed in low yield or be wholly ineffective. A few of such multifunctional aromatic compounds include fluorine-18 labeled 6-fluoro-L-DOPA, 2-fluorotyrosine, 6-fluoronorepinephrine, and 6-fluoro-metaraminol. Prior to the present invention, the only known practical synthetic route for a number of these molecules involved the use of the electrophilic fluorinating reagents, either fluorine-18 labeled elemental fluorine, or acetylhypofluorite. The use of these two reagents results in low specific activity, and direct fluorination usually produces a mixture of fluorinated products.